Salmonella pathogenicity island 1 knockdown confers protection against myocardial fibrosis and inflammation in uremic cardiomyopathy via down-regulation of S100 Calcium Binding Protein A8/A9 transcription

Abstract

Background/Aim Uremic cardiomyopathy (UCM) is a characteristic cardiac pathology that is commonly found in patients with chronic kidney disease. This study dissected the mechanism of SPI1 in myocardial fibrosis and inflammation induced by UCM through S100A8/A9. Methods An UCM rat model was established, followed by qRT-PCR and western blot analyses of SPI1 and S100A8/A9 expression in myocardial tissues. After alterations of SPI1 and S100A8/A9 expression in UCM rats, the blood specimens were harvested from the cardiac apex of rats. The levels of creatine phosphokinase-MB (CK-MB), blood creatinine, blood urea nitrogen (BUN), and inflammatory cytokines (interleukin [IL]-6, IL-1β, and tumor necrosis factor-α [TNF-α]) were examined in the collected blood. Collagen fibrosis was assessed by Masson staining. The expression of fibrosis markers [transforming growth factor (TGF)-β1, α-smooth muscle actin (SMA), Collagen 4a1, and Fibronectin], IL-6, IL-1β, and TNF-α was measured in myocardial tissues. Chromatin immunoprecipitation and dual-luciferase reporter gene assays were conducted to test the binding relationship between SPI1 and S100A8/A9. Results S100A8/A9 and SPI1 were highly expressed in the myocardial tissues of UCM rats. Mechanistically, SPI1 bound to the promoter of S100A8/A9 to facilitate S100A8/A9 transcription. S100A8/A9 or SPI1 knockdown reduced myocardial fibrosis and inflammation and the levels of CK-MB, blood creatinine, and BUN, as well as the expression of TGF-β1, α-SMA, Collagen 4a1, Fibronectin, IL-6, TNF-α, and IL-1β in UCM rats. Conclusion SPI1 knockdown diminished S100A8/A9 transcription, thus suppressing myocardial fibrosis and inflammation caused by UCM.

Advances in the study of S100A9 in cardiovascular diseases

“…and the expression of inflammatory cytokines (IL-6, TNF-α, and IL-1β) in both the local myocardium and systemic circulation was reduced. 130 These indicate that knockdown of S100A9 can alleviate the inflammatory response and tissue fibrosis in UCM, thereby improving cardiac function. 130 AF is a common arrhythmia caused by various factors such as inflammation and atrial fibrosis.…”

“…130 These indicate that knockdown of S100A9 can alleviate the inflammatory response and tissue fibrosis in UCM, thereby improving cardiac function. 130 AF is a common arrhythmia caused by various factors such as inflammation and atrial fibrosis. 131 Liu et al 133 identified S100A9…”

“…[126][127][128] Importantly, inflammatory reactions have closely implicated in hypertrophic cardiomyopathy (HCM), uremic cardiomyopathy (UCM), and AF. [129][130][131] In HCM, Zhao et al 132 identified immune infiltration-related genes through RNA sequencing, discovering that S100A9 is predominantly expressed by infiltrating M1 macrophages in the cardiac immune microenvironment, especially CCR2-M1 macrophages, and also confirmed that S100A9 is a potential biomarker for differentiating HCM from controls. But its specific molecular mechanism remains to be further explored.…”

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy

“…192 Potential mechanisms related to myocardial fibrosis in CKD include apoptosis, inflammation, oxidative stress, or renin-angiotensin-aldosterone system activation 193 and may involve FGF23, Klotho, or SPI-1 (salmonella pathogenicity island 1) signaling. 194,195 Metabolic Alterations in the Uremic Heart Structural remodeling in the uremic heart is accompanied by various changes in cardiac metabolism (Figure 2). Recent metabolic studies have revealed disturbances in cardiac energetics and further central processes such as oxidative stress and Ca 2+ handling.…”

“…192 Potential mechanisms related to myocardial fibrosis in CKD include apoptosis, inflammation, oxidative stress, or renin-angiotensin-aldosterone system activation 193 and may involve FGF23, Klotho, or SPI-1 (salmonella pathogenicity island 1) signaling. 194,195…”